The fundamental objectives of the proposed research are: (1) to provide a better understanding of the actions of the narcotic analgesics in man through a definition of the pharmacokinetics of these drugs in human subjects, (2) to improve the anesthetic management with narcotic analgesics of non-tolerant and tolerant patients, and (3) to identify clinically significant alterations in the responses to anesthesia of patients engaged in the non-medical use of drugs and abuse of alcohol. The basic approach to these objectives involves correlation of plasma and estimated brain concentrations of selected narcotic analgesics with their pharmacological effects in naive as well as in drug dependent human subjects. Adequate correlations of biological actions with the disposition of these drugs in vivo will enable us: (1) to define dosage regimens for the optimal use of the narcotic analgesics intraoperatively and postoperatively in non-tolerant and tolerant patients with the avoidance of complications secondary to accumulation of these drugs, (2) to increase our understanding of the factors influencing the placental transfer of the narcotic analgesics, (3) to improve the clinical management of the neonatal abstinence syndrome, (4) to investigate the basis of clinically significant interactions of the narcotic analgesics with other drugs including the narcotic antagonists, and (5) to study the development of acute tolerance to large intravenous doses of narcotic analgesics as they are currently used in certain anesthetic practices. Sufficiently sensitive and specific methods of analysis for the narcotic analgesics in biological specimens will utilize solvent extraction procedures in conjunction with gas chromatography, radioimmunoassay and other radioisotopic techniques. The anesthetic setting with extensive monitoring of physiologic and biochemical functions in human subjects will facilitate correlations of the biological disposition of the narcotic analgesics with their pharmacological effects. In addition to improving patient care, this study will contribute basic, quantitative information concerning the actions of the narcotic analgesics in man.